CN1033521A - Novel 2-guanidine radicals thiazolium compounds and preparation method thereof, and the intermediate that is used as Famotidine pyridine preparation technology - Google Patents
Novel 2-guanidine radicals thiazolium compounds and preparation method thereof, and the intermediate that is used as Famotidine pyridine preparation technology Download PDFInfo
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- CN1033521A CN1033521A CN88104081A CN88104081A CN1033521A CN 1033521 A CN1033521 A CN 1033521A CN 88104081 A CN88104081 A CN 88104081A CN 88104081 A CN88104081 A CN 88104081A CN 1033521 A CN1033521 A CN 1033521A
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- silyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 73
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 24
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229960001596 famotidine Drugs 0.000 title claims abstract description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 17
- 238000005516 engineering process Methods 0.000 title description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 55
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 53
- 238000000034 method Methods 0.000 claims description 42
- -1 methoxyl group Chemical group 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 16
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 229940124530 sulfonamide Drugs 0.000 claims description 14
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 11
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 8
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims description 7
- 150000001409 amidines Chemical class 0.000 claims description 7
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 6
- 238000006884 silylation reaction Methods 0.000 claims description 6
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- VZWOXDYRBDIHMA-UHFFFAOYSA-N 2-methyl-1,3-thiazole Chemical compound CC1=NC=CS1 VZWOXDYRBDIHMA-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 4
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 4
- UJMWUVWZCDUPPH-UHFFFAOYSA-N 5-silyl-2H-1,3-oxazol-2-id-4-one Chemical compound [SiH3]C1C(N=[C-]O1)=O UJMWUVWZCDUPPH-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 150000005451 methyl sulfates Chemical class 0.000 claims description 3
- 229950000081 metilsulfate Drugs 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- ISNICOKBNZOJQG-UHFFFAOYSA-N 1,1,2,3,3-pentamethylguanidine Chemical compound CN=C(N(C)C)N(C)C ISNICOKBNZOJQG-UHFFFAOYSA-N 0.000 claims description 2
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 2
- ZQFIAAFKCPCOQZ-UHFFFAOYSA-N 2-chloro-2,3-dimethylbutane silane Chemical compound [SiH4].CC(C(C)(C)Cl)C ZQFIAAFKCPCOQZ-UHFFFAOYSA-N 0.000 claims description 2
- ZRAPHEBMDYQXKR-UHFFFAOYSA-N 2-trimethylsilylisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N([Si](C)(C)C)C(=O)C2=C1 ZRAPHEBMDYQXKR-UHFFFAOYSA-N 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- KQJQICVXLJTWQD-UHFFFAOYSA-N N-Methylthiourea Chemical compound CNC(N)=S KQJQICVXLJTWQD-UHFFFAOYSA-N 0.000 claims description 2
- YKFRUJSEPGHZFJ-UHFFFAOYSA-N N-trimethylsilylimidazole Chemical compound C[Si](C)(C)N1C=CN=C1 YKFRUJSEPGHZFJ-UHFFFAOYSA-N 0.000 claims description 2
- VNSDCKWDEWZCBP-UHFFFAOYSA-N NS([SiH3])(=O)=O Chemical compound NS([SiH3])(=O)=O VNSDCKWDEWZCBP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- ACTAPAGNZPZLEF-UHFFFAOYSA-N chloro(tripropyl)silane Chemical compound CCC[Si](Cl)(CCC)CCC ACTAPAGNZPZLEF-UHFFFAOYSA-N 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- AATYKEFFPLPLST-UHFFFAOYSA-N trimethylsilylurea Chemical compound C[Si](C)(C)NC(N)=O AATYKEFFPLPLST-UHFFFAOYSA-N 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- 239000001301 oxygen Substances 0.000 claims 3
- 229910052760 oxygen Inorganic materials 0.000 claims 3
- 241000370738 Chlorion Species 0.000 claims 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 1
- DDDZJQQABMXUPK-UHFFFAOYSA-N [SiH3]NS(=O)=O Chemical compound [SiH3]NS(=O)=O DDDZJQQABMXUPK-UHFFFAOYSA-N 0.000 claims 1
- 125000005103 alkyl silyl group Chemical group 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims 1
- FZHAPNGMFPVSLP-UHFFFAOYSA-N silanamine Chemical compound [SiH3]N FZHAPNGMFPVSLP-UHFFFAOYSA-N 0.000 claims 1
- 150000004756 silanes Chemical class 0.000 claims 1
- 230000028327 secretion Effects 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 16
- 150000002463 imidates Chemical class 0.000 description 14
- 238000001035 drying Methods 0.000 description 7
- 238000002329 infrared spectrum Methods 0.000 description 7
- 238000001556 precipitation Methods 0.000 description 7
- 238000005755 formation reaction Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000013019 agitation Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 3
- 150000002541 isothioureas Chemical class 0.000 description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 3
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000004454 trace mineral analysis Methods 0.000 description 3
- QCBZCEKWIGTIMT-UHFFFAOYSA-N 1,3-bis(sulfanyl)propan-2-one Chemical compound SCC(=O)CS QCBZCEKWIGTIMT-UHFFFAOYSA-N 0.000 description 2
- SUNMBRGCANLOEG-UHFFFAOYSA-N 1,3-dichloroacetone Chemical compound ClCC(=O)CCl SUNMBRGCANLOEG-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 2
- ZUZBCIXCPNLAOU-UHFFFAOYSA-N Cl[NH] Chemical compound Cl[NH] ZUZBCIXCPNLAOU-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000005828 desilylation reaction Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- PLXPTFQGYWXIEA-UHFFFAOYSA-N nitroformonitrile Chemical compound [O-][N+](=O)C#N PLXPTFQGYWXIEA-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003419 tautomerization reaction Methods 0.000 description 2
- 150000007944 thiolates Chemical class 0.000 description 2
- VGBAYGFELCUXBS-UHFFFAOYSA-N 1,4-dioxane-2-carboxylic acid Chemical compound OC(=O)C1COCCO1 VGBAYGFELCUXBS-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- ZHAKAIBZKYHXJS-UHFFFAOYSA-N 2-(chloromethyl)-1,3-thiazole Chemical compound ClCC1=NC=CS1 ZHAKAIBZKYHXJS-UHFFFAOYSA-N 0.000 description 1
- IRTCJFCIQKNFPP-UHFFFAOYSA-N 2-methyl-1,4-dioxane Chemical compound CC1COCCO1 IRTCJFCIQKNFPP-UHFFFAOYSA-N 0.000 description 1
- MQJZSMLAUBXNGZ-UHFFFAOYSA-N 4-(methoxymethyl)-1,3-thiazole Chemical compound COCC1=CSC=N1 MQJZSMLAUBXNGZ-UHFFFAOYSA-N 0.000 description 1
- NESKCZJINZUBPH-UHFFFAOYSA-N 4-trimethylsilylisoindole-1,3-dione Chemical compound C[Si](C)(C)C1=CC=CC2=C1C(=O)NC2=O NESKCZJINZUBPH-UHFFFAOYSA-N 0.000 description 1
- UZAOOCPKYMGRHG-UHFFFAOYSA-N 5-(chloromethyl)-1,3-thiazole Chemical compound ClCC1=CN=CS1 UZAOOCPKYMGRHG-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
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- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
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- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
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- 238000011109 contamination Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
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- 230000002939 deleterious effect Effects 0.000 description 1
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- OKGXJRGLYVRVNE-UHFFFAOYSA-N diaminomethylidenethiourea Chemical compound NC(N)=NC(N)=S OKGXJRGLYVRVNE-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
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- 230000000694 effects Effects 0.000 description 1
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- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 1
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- 238000011065 in-situ storage Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 235000019633 pungent taste Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012207 quantitative assay Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- BUVBYQUZAIPDHT-UHFFFAOYSA-N thiourea Chemical class NC(N)=S.NC(N)=S BUVBYQUZAIPDHT-UHFFFAOYSA-N 0.000 description 1
- VJAMCQFRFWRULO-UHFFFAOYSA-N thiourea;dihydrochloride Chemical compound Cl.Cl.NC(S)=N VJAMCQFRFWRULO-UHFFFAOYSA-N 0.000 description 1
- XJVIPPHGDPEDJL-UHFFFAOYSA-N thiourea;hydrochloride Chemical compound Cl.NC(N)=S XJVIPPHGDPEDJL-UHFFFAOYSA-N 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- VYGSFTVYZHNGBU-UHFFFAOYSA-N trichloromethanesulfonic acid Chemical group OS(=O)(=O)C(Cl)(Cl)Cl VYGSFTVYZHNGBU-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/18—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides 2-guanidine radicals-thiazolium compounds of a kind of novelty and preparation method thereof, the structure that changes compound can be by general formula I
(R in the formula
0Be hydrogen atom or low-molecular-weight alkyl, m is 2 to 7, and n is 2 to 4) or general formula V (R is low-molecular-weight alkyl in the formula) expression, compound of the present invention is the important intermediate of a kind of preparation Famotidine pyridine (at the inhibitor that medically is used as stomachial secretion) usefulness.
Description
2-guanidine radicals-4-thyroidan compound can be used for preparing N-sulfamyl-3-[(2-guanidine radicals thiazole-4-yl) methylthio group)-intermediate of propionyl amidine, known N-sulfamyl-3-[(2-guanidine radicals thiazole-4-yl already) methylthio group)-the propionyl amidine has the characteristic that suppresses stomachial secretion.
Application number be in the patent documentation of ES8700719 2-guanidine radicals-4-chloromethyl-thiazole has been described and the sodium sulfhydrate for preparing at once between reaction.And JP 6618,774(CA.105:60596V) method described in the patent documentation is chiefly directed under the existence of hydrogen sulfide, finishes Dyhard RU 100 and 1, the reaction of 3-dimercapto acetone, wherein 1,3-dimercapto acetone is that the salt of 3-Dichloro acetone and hydrogen sulfide reacts and prepares by 1.Above-mentioned these methods are because of relating to the operation of deleterious inflammableness hydrogen sulfide, and will carry out disaggregating treatment as remaining waste water (gas) when emitting at it later on, so the inconvenience part is arranged.This class methods main difficulty is by corresponding sulfide, the formed reaction mixture of disulphide, and under the situation of 5-chloromethyl thiazole, it is to the conversion of 4-methoxymethyl thiazole.Secondly the product system that also is gained carries out quantitative assay by iodometry, and this product is negative in the mercaptan check of carrying out with the nitro prussiate (activity).All these will cause low yield and low-purity.
Additive method relates to sodium hydroxide makes S-(2-guanidine radicals-4-thiazolyl methyl) the dihydrochloride hydrolysis of isothiourea, generate 2-guanidine radicals-4-mercapto methyl thiazole on the spot.Some pieces of patent documentations are described the preparation method of this isothiourea (isothiouronium) salt.For example, GB 2052478A and 2055800 A have described 3-(2-aminothiazole-4-base-methylthio group)-preparation method of propionitrile; EP87,274(GB 82/5075), ES 519,936 and EPO 128,736(JP 83/102,206) 3-(2-guanidine radicals thiazole 4-methylthiol described)-preparation method of propionitrile; And US 4.496.737 and ES 540352 have described the preparation method of N-sulfamyl-propionyl amidine derivative.
The easily oxidizable of the thiolate that is generated in the alkaline medium of sodium hydroxide has caused the formation of disulphide and other impurity.S-(2-guanidine radicals-thiazole-4-base-methyl) hydrolysis at room temperature can take place in the dihydrochloride of isothiourea, and heating will be accelerated this process.In the above two kinds of cases, for using the sodium hydroxide part, use acid for adjusting pH value, to be settled out brown viscosity oily matter thus, this material is difficult to operation, is easy to oxidation, in many organic solvents, all do not dissolve (for example methylene dichloride), thereby be difficult to effectively separate by extraction.
The current methods of (in situ) generation thiolate also shows another weak point on the spot, and promptly some impurity will pollute the isothiourea compound as starting material.All these impurity will appear in the final reacting product more or less.
Known to the skilled person in this field, amidinothiourea and 1,3-Dichloro acetone (carcinogenic substance) compound has toxicity, pungency and causes skin and mucous membrane blisters, and the anaphylaxis that can produce dermatitis and so on when operation 2-guanidine radicals-4-5-chloromethyl thiazole.All these materials are pollutent, are present in the isothiourea derivatives, and the latter can cause the reaction with chloromethyl-thiazole.
Generating 3-(2-guanidine radicals-thiazole-4-base-methylthio group with isothiourea compound reaction except above-mentioned) the impurity that produced in the process of propionitrile, changing into 3-(2-guanidine radicals-thiazole-4-base-methylthio group) also generated other products in the process of propionyl imido-ester (Propionimidate).
S.R.Sandler and W.Karo(Organic Functional Group Preparations, Academic Press, New York 1972) and R.Roger and D.G.Neilson(The Chemistry of Imidates; Chem.Rev.61, pgs.181,183,184; 1961) summarized the preparation method of imido-ester (imidate) already.According to these authors' viewpoint, moisture will cause the generation of ester, can produce acid amides under the condition of heating, and excessive alcohol will make it to form ortho ester and ammonium chloride.In addition, from experimental result, it is suspectable using thinner whether can cause low yield, and in some cases, afterwards a couple of days is added to it in reaction mixture again can be recommended in reaction.
With regard to 3-(2-guanidine radicals-thiazole-4-base-methylthio group)-propionitrile with regard to, it in 3 °-6 ℃ temperature and methanol solution with the reaction of hydrochloric acid except that generating imido-ester, also produce other compounds.The thinner that uses in the reaction process has chloroform, methylene dichloride or toluene and so on, and for the propionitrile of each mole, the consumption of hydrochloric acid is the 5-20 mole, and methyl alcohol is the 30-37 mole, and selected thinner consumption is double volume.The result shows, from 105.0 gram (purity of mensuration is 95%) 3-(2-guanidine radicals-thiazoles-4-base-methylthio group) separate the thick product that obtains about 90.0 grams the propionitrile.Handle with methylene dichloride then, filter back generation 50.0 grams and pollute the imido-ester that ester and nitrile are arranged; The ester that obtains about 40.0 grams will be separated behind the methylene dichloride evaporate to dryness.
In some other experiment, depend on the volumetric molar concentration of hydrochloric acid in the time-continuing process, separable 25% compound and the acid amides of obtaining without discriminating, the former is shallow cream color, and decomposition temperature is 220 ℃ (decomposing the back color deepens greatly), and the latter is 200 ℃ of decomposition.
Another disagreeable part is reflected in the reaction of imido-ester and sulphonamide, and this will jeopardize the quality product of relevant yield and purity aspect.Various competing reactions will change this two kinds of situations as the dipolymer of third amidine derivative, propionyl imido-ester-third amidine and formation reaction with dipolymer and so on of sulphamide bridged bond.EPO 128,736 patent documentations have been described the reaction in methyl alcohol during three days, temperature of reaction is 20 °-30 ℃, separating obtained crude reaction product recrystallization in dimethyl formamide-water, then by means of alkali, from its acetate aqueous solution, Famotidine pyridine (famotidine) precipitation is separated out, yield is 48.8%.According to the inventor's experimental result, prepare a kind of dystectic polymorphic form thus, it is at 3400-3000cm
-1The corresponding analysis result that infrared spectra (KBr) analytical data in the zone and characteristic X-ray grating spectrum are different from the low melting point polymorphic form.
By method of the present invention, these problems are solved.This method both had been different from preceding method, also was different from those methods described in the scientific and technical literature, and it is that new product and reagent are used for β-cyanoethylation reaction, the imido-ester formation reaction, and to the conversion reaction of sulphonamide.
Method of the present invention comprises:
(a) by the salt of 2-guanidine radicals-4-mercapto methyl-thiazole and the formed a kind of novelty of bicyclic amidine, said bicyclic amidine preferably 1,8-diaza-bicyclo [5.4.0] 11 carbon-7-alkene (DBU) or 1,5-diaza-bicyclo (4.3.0) ninth of the ten Heavenly Stems-5-alkene (DBN).These salt immediately with acrylonitrile reactor, in the aqueous solution, form 3-and replace propanenitrile derivatives, in fact have quantitative yield;
(b) by hydrochloric acid Yu a kind of novel hydrochloric acid oxygen reagent that diox prepares, be used for generating the imino-chlorine (inidoyl chloride) of deriving and obtaining by aforementioned two nitriles in the original place, the latter and methyl alcohol situ reaction produce corresponding propionyl imido-ester, and have good selectivity; With
(c) under moderate moisture, by N, a kind of new reaction takes place with N-trimethyl silyl imide salts in N '-two-trimethyl silyl-sulphonamide in non-hydroxyl solvent (preferably acetonitrile, diox, N,N-DIMETHYLACETAMIDE, methylene dichloride or chloroform), after the distillation, promptly obtain the Famotidine pyridine.
The invention describes a kind of 2-guanidine radicals thiazolium compounds of novelty, and be used as the application of the intermediate of preparation Famotidine pyridine.
According to the present invention, it provides a kind of following general formula that has
The product of 2-guanidine radicals thiazole, R in the formula
OBe hydrogen base or low-molecular-weight alkyl, m is 2 to 7, and n is 2 to 4.
So-called lower molecular weight is meant the straight chain type that contains 1 to 5 carbon atom or the group of branched chain type.This class group can comprise methyl, ethyl, sec.-propyl or the tertiary butyl etc.
And the compound of formula I is a kind of base addition salt that can exist with the tautomerism type form.
Said base addition salt comprises the salt of the sulfhydryl compound with amidino groups organic bases, and m is 2 to 7 herein, and n is 2 to 4.Preferably select 1 for use, 8-diazacyclo [5.4.0] 11 carbon-7-alkene (DBV), 1,5-diaza-bicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN) etc.
By the hydrolysis under controlled conditions of following compound, can prepare the compound of formula I easily, these compounds are:
S-(2-guanidine radicals-thiazole-4-base-methyl) amidino groups isothiourea, S-isothiourea, S-(N-methyl) isothiourea or other derivatives (described in the inventor's the Spain patent application ES8700719).Described hydrolysis ties up under the existence of water and bicyclic amidine (being selected from the compound of DBN, DBU and so on), finishes in the inert solvent of acetonitrile, diox, Virahol (or their mixed solution) and so on.
The consumption of water is perhaps used the water until excessive 10% by stoichiometric ratio in the above-mentioned reaction, and the consumption of bicyclic amidine such as is at a mol ratio.If with other mineral alkali or organic bases when neutralizing the hydrochloric acid isothiourea initial, only need be with normal DBU or DBN etc.Be used for oxyhydroxide, carbonate or supercarbonate that this kind purpose mineral alkali can be selected from sodium or potassium, or alkali-metal pure oxide compound (alkaline alcohoxide); Organic bases then can be selected primary amine, secondary amine, tertiary amine and heterocyclic amine for use, and wherein the preferably can exemplify as follows: triethylamine, diethylamine, tetramethyl guanidine and pentamethyl-guanidine.
Salt with molecular formula I structure, its formation reaction is quite fast, and can be precipitated out from reaction mixture immediately.Conversion process is actually quantitatively carries out, and selectivity also is so, can reach 95% separation rate in theory.Reaction times can change, and in 60 to 180 minutes scope, need not extraneous energize.
Vinyl cyanide is added in the aqueous solution of salt of molecular formula I, then produces 3-(2-guanidine radicals-thiazole-4-base-methylthio group rapidly) the propionitrile precipitation, this conversion process almost is quantitative.Filtered and recycled bicyclic amidine from the aqueous solution, and repeated application more in the method.
Other compounds of the present invention can be by 3-(guanidine radicals-thiazole-4-base-methylthio group) propionitrile and molecular formula be
Oxonium salt reaction and prepare, X is chlorine, bromine, metilsulfate or trichloromethyl sulfonate in the following formula; R
1Be hydrogen atom, methyl, ethyl or phenyl; O is 1-2; And p is 2-3.In above-mentioned reaction, 1 of capacity is preferably arranged, 3-diox or 1,4-diox.Under above-mentioned two kinds of situations, use excessive De diox, can obtain containing the compound solution of the molecular formula II of 20%-30% hydrogen-oxygen salt.In this class salt, preferably be suitable for the muriate, bromide or the metilsulfate that Cong diox and corresponding acid, prepare.
Excessive De diox also is used as the thinner of the compound of molecular formula II, and is used for such as having following molecular formula
The preparation of compounds of halo imines, the Z in the formula III is the chlorine or bromine atom; R
0Implication the same.
The compound of molecular formula III can not separate, if the formation of this compound is to exist under the methyl alcohol situation of adjustment amount, the Z group in the compound of this molecular formula III that is then produced is a methoxyl group.In other cases, as described in the inventor's the Spain patent application ES 8702202, though because of the high reactivity of imino-chlorine, its precipitation is feasible with separating.Reaction is proceeded, until generating imido-ester.If these reactions are to carry out in the presence of thinner such as methylene dichloride, chloroform or excessive methanol, then the generating rate of the compound of molecular formula III is very slow, and yield is low.
If carry out under the above-mentioned existence that is reflected at ammonia or ammonium chloride, then produce amidine with molecular formula III structure, Z be an amino herein.
The compound of molecular formula II and used 3-(2-guanidine radicals-thiazole-4-base-methylthio group) mol ratio of propionitrile can change in the scope of 3-7.The content of methyl alcohol is adjusted to the degree of the compound dissolution of molecular formula III.Imido-ester generates the required time, is 6-20 hour under 3 ℃-10 ℃ temperature.Perhaps, the hydrochloride of the propionitrile that initial 3-replaces or sulphate form are to be difficult for difference.Segregative line adopts ordinary method to carry out.
The final step of this method is characterised in that compound of molecular formula III (Z is a methoxyl group) and silylating agent phase reaction obtain having following molecular formula herein
The tautomerism liquid solution of structure, wherein R
0Implication the same, and R is the alkyl that contains the straight or branched of 1 to 5 carbon atom.
Make the compound and the N-trialkylsilkl sulphonamide (VI) of molecular formula IV
Carry out chemical combination, can obtain having following molecular formula
The solution of structural compounds, wherein R
0With the implication of R all with last with, the molecular formula V is represented a kind of possible tautomer.
The silylation agent that is applicable to preparation N-trialkylsilkl imido-ester (IV) and N-trialkylsilkl sulphonamide (VI) can be selected from following compounds: hexamethyldisilazane, 3-trimethyl silyl-2-oxazolidone, 1,3-pair-the trimethyl silyl urea, N, O, two-the trimethyl silyl ethanamide, N-trimethyl silyl ethanamide, N-trimethyl silyl saccharin, N-trimethyl silyl phthalimide, the trimethyl silyl biuret, N-trimethyl silyl pyrroles, N-trimethyl-silyl-imidazole quinoline, trimethylchlorosilane, chlorotriethyl silane, the tripropyl chlorosilane, dimethyl tertiary butyl chloride silane, N, N '-two-trimethyl silicane alkyl sulfonamide, N, N '-four-trimethyl silyl sulphonamide, N, N '-two-dimethyl tertiary butyl silyl sulphonamide, N, O-pair-trimethylammonium sulphonamide etc.
The compound VI can be a kind of N-trialkylsilkl derivative, the derivative of N-trimethyl silylization single, double or three-replace preferably, and this depends on the amount of silylating agent and trialkyl sulphonamide.With regard to the imido-ester III (Z is a methoxyl group) of each mole, the consumption of this material can be in the normal scope of 1.5-4.0.Solvent system is selected from any in this group of being made up of acetonitrile, diox, methylene dichloride, chloroform and N,N-DIMETHYLACETAMIDE and so on non-hydroxyl solvent.Above-mentioned this kind solvent and molecular formula are the generation objectionable intermingling of the compound of IV, V and VI.
Alcohol (being selected from methyl alcohol, ethanol, Virahol or propyl carbinol) with equivalent is handled the reaction solution that is produced, so that the compound V is carried out the desilylation reaction, reaction ties up under the room temperature to be carried out, simultaneously with stirring.After the reaction, filtered, and used methanol wash, obtained the Famotidine pyridine thus.Conversion process is actually quantitatively carries out, and selection rate is 82%, and separating yield is 70%.As long as undertaken by the method described in the inventor's the Spain application ES 8702020, can produce required polymorphic form.
Embodiment 1
1-8-diazacyclo [5.4.0] 11 carbon-7-alkene and 2-guanidine radicals-4-mercapto methyl-thiazole salt (DBU salt)
(A) under agitation, to S-(2-guanidine radicals-thiazole-4-base-methyl) isothiuronium salts acidulants (75.80 grams; 0.25 mole) in the suspension in acetonitrile (240 milliliters) and the water (4.86 milliliters, 0.27 mole), once add whole DBU(130.5 milliliters, 0.87 mole).Along with temperature rises to 40 ℃ from 20 ℃, almost produce a large amount of throw outs immediately, reaction mixture is continued to stir for some time (length of time depends on stirring efficiency, in 120-180 minute scope), makes its temperature reduce to room temperature.Product after filtering, use acetonitrile and methylene dichloride (or Virahol) washing successively, dry under vacuum then, obtain the compound shown in the 76.6-80.9 gram present embodiment title thus, yield is 90%-95%, and fusing point is 152-155 ℃ (d) (color burn in the time of 140 ℃-150 ℃).Check with the nitro cyanide solution is positive, and purity is 95.0-98.0%(iodometry titration) infrared spectra (KBr) ν cm
-1: intensity (intense) and width indicating value are 3400 to 2200(to have inferior light belt, and the center is about 3000), eigenwert is at 1630(s), 1570(s), 1450(s) and 1210(s).
Trace analysis (C
14H
24N
6S
2; Molecular weight=340.50) result is as follows: calculated value is C, 49.3; H, 7.1; N, 24.7, and experimental value is C, 49.0; H, 7.2; N, 24.5; S, 19.0.
S-(2-guanidine radicals-thiazole-4-base-methyl with equivalent)-and the dihydrochloride of N-methyl-isothiourea replaces aforesaid isothiourea, the compound shown in the present embodiment title that obtains thus, and its speciality is identical with above-claimed cpd, and yield is also roughly the same.
Replace acetonitrile with Virahol (100 milliliters), after adding DBU, produce supersaturated solution, under 32 ℃ of temperature,, begin precipitation immediately then with the inoculation of DBU salt crystal.Obtain the compound shown in the present embodiment title after the separation, yield is 75%.
(B) according to the method described in the present embodiment I A, with S-(2-guanidine radicals-thiazole-4-base-methyl) miaow base isothiuronium salts acidulants (86.30 grams, 0.25 mole) replace isothiourea derivatives, compound shown in the present embodiment title that obtains thus, its character is identical with above-claimed cpd, and yield also roughly the same.Amidino groups isothiourea (dihydrochloride) is with following method preparation: (1) makes 1, and the 3-Dichloro acetone reacts with 2 times of normal miaow base isothioureas in ethanol; Perhaps (2) make it the mixture heating up of miaow base isothiourea in Virahol of 2-guanidine radicals-4-chloromethyl-thiazole and equivalent 60 minutes react.Under above-mentioned arbitrary situation, remove alcohol after, promptly obtain isothiourea compound (semi-solid state), this product need not to carry out aforesaid purification), the use that can pay.
S-(2-guanidine radicals-thiazole-4-base-methyl) (molecular weight is 345,26 to miaow base isothiourea; C
7H
12N
8S
2Trace analysis result 2HCl) is as follows: calculated value is C, 24.3; H, 4.2; N, 32.4; S, 18.6; Cl, 20.5, experimental value is C, 24.5; H, 4.0; N, 32.9; S, 18.9; Cl, 20.9.
If replace above-mentioned isothiourea with xanthogenate, the compound shown in the present embodiment title of gained then, its character and above-mentioned product type are same.
(C) acetonitrile (75 milliliters) solution to 2-guanidine radicals-4-mercapto methyl-thiazole (18.82 gram, 0.1 mole) adds DBU(16.7 milliliter, 0.11 mole), produce the precipitation of DBU salt immediately.After at room temperature stirring for some time (30 minutes), filter, and (25 milliliters) and methylene dichloride (25 milliliters) washing of using acetonitrile in succession.Obtain the compound shown in the present embodiment title of quantitative yield thus, its character is identical with product among the embodiment 1A.
Make 1,3-dimercapto acetone and equivalent Dyhard RU 100 (Japanese Patent JP 6118,774) react in acetonitrile, add DBU to above-mentioned reaction product then, impel the compound shown in the present embodiment title to precipitate thus.
Embodiment 2
1,5-diaza-bicyclo [4,3,0] ninth of the ten Heavenly Stems-5-alkene and 2-guanidine radicals-4-mercapto methyl-thiazole salt (DBN salt)
Under agitation, to S-(2-guanidine radicals-4-thiazolyl methyl) dihydrochloride of isothiourea (12.13 grams, 0.04 add entry (0.81 milliliter, 0.045 mole) and DBN(16.2 milliliter in succession, 0.13 mole in acetonitrile (30 milliliters) suspension mole)).Along with after temperature reaches about 45 ℃ from initial 25 ℃, reactant almost completely dissolves, and begins precipitation rapidly thereupon.Reaction mixture was stirred 120-180 minute, make temperature reduce to 20 ℃.Filtered subsequently, and with acetonitrile and washed with dichloromethane, after the drying that reduces pressure down, obtain the compound shown in the present embodiment title of 11.80 grams (yield is 94.5%), fusing point is 127-129 ℃.Infrared spectra (KBr) ν cm
-1: the width indicating value is that 3500-2600(has inferior light belt), the amplitude indicating value is 1700-1500, at 1665(s), 1630(w), 1600(m) and 1530(s) light belt place.
(C
12H
20N
6S
8, molecular weight is 312.45) the trace analysis result as follows: calculated value is C, 46.1; H, 6.4; N, 26.9, S, 20.5; Experimental value is C, 46.3; H, 6.5; N, 27.0; S, 20.2.
Above-mentioned this salt will transform along with the time, and the nitro cyanide test is negative, and in the presence of the sodium hydroxide and vinyl cyanide of equivalent, after (30 minutes), generate corresponding propanenitrile derivatives through after a while.
Embodiment 3
3-(2-guanidine radicals-thiazole-4-base-methylthio group) propionitrile
(A) press embodiment 1 described method, the DBU salt [68.2 grams, or 74.1 grams (be through washed with dichloromethane gained purity 92% salt), 0.20 mole] of preparation recently is dissolved in 300 ml waters.With ice-water-bath cooling, temperature of reaction is controlled at 20 °-25 ℃, and adds vinyl cyanide (16.50 milliliters, 0.25 mole) gradually, in 5 minutes, add and finish.Under agitation, white depositions almost appears in the reaction mixture immediately.Finish along with vinyl cyanide all adds, in fact reaction also stops thereupon, and the test of nitro prussiate is negative.Stirred 15 minutes, and be cooled to 15 ℃-20 ℃, filter then, give drying after washing with water, finally obtain the compound shown in 45.0 gram (yield is 93.3%) present embodiment titles, fusing point is 127-129 ℃ (fusing point is 132 ℃ behind the recrystallization); Infrared spectra (KBr) ν cm
-1: 3420(s), 3230(w), 3080(m), 2220(m), 1630(s), 1590(s), 1535(s) and 1450(s).
(B) press the described method of embodiment 3A, replace DBU salt with DBN salt (embodiment 2,70.0 grams are to prepare recently, and the process washing).The pH value of the mixed solution that DBN salt and acrylonitrile reactor is produced with 36% hydrochloric acid (about 0.20 mole) is adjusted to 8.0-8.5.Throw out through separate and drying after, promptly obtain having the compound shown in the present embodiment title of same nature, its yield also roughly the same.
Embodiment 4
3-(2-guanidine radicals-thiazole-4-base-methylthio group) propionyl imino-chloro-hydrochloride
Under room temperature (20 ℃-25 ℃), with 3-(2-guanidine radicals-thiazole-4-base-methylthio group) propionitrile compound (41.02 gram, 0.17 mole) divides and is added to 1 three times, 4-dioxanate acidulants [1[100.0 gram, HCl 25%(is by weight), 0.68 mole) in.Stir after 120 minutes, be cooled to 0-5 ℃, obtain pasty mixture thus, be equivalent to the compound shown in the present embodiment title.
Embodiment 5
Methyl-3-(2-guanidine radicals-thiazole-4-base-methylthio group) propionyl inferior amine salt
(A) under fully stirring, in being cooled to 0-5 ℃ the mixture of embodiment 4, add 40 milliliters of anhydrous methanols (about 0.1 mole) gradually, and remain under this temperature.Formed thus solution is after stirring 8-20 hour under 5 ℃, gradually it is added to by sodium hydroxide (13.3 grams, 97%, 0.33 mole) and in the formed cold mixt of solution (0 ℃-10 ℃) of anhydrous sodium carbonate (37.1 restrain, 0.35 mole) in water (700 milliliters) and methylene dichloride (300 milliliters).After stirring 60 minutes under 10 ℃, filter, and use a large amount of water (500 milliliters), acetonitrile and washed with dichloromethane in succession.After the drying, promptly obtain the compound shown in the 37.2 gram present embodiment titles, yield is 80%, and fusing point is 130-135 ℃ (after being heated, be suspended in the second eyeball, fusing point is 136-138.5 ℃).
The organic phase that of inclining is removed moisture with anhydrous sodium sulphate, and steams solvent, reclaims and obtains the thick product of another part, after washed with dichloromethane and drying, can recycle for present method.
(B) press the described method of embodiment 4A and 5A, with 1, the 3-diox replaces 1, and the 4-diox obtains thus corresponding to the compound shown in the present embodiment title, and its yield and character are all with roughly the same above-mentioned.
(C) with 1,4-dioxanate acidulants [42.0 grams, 30%(by weight), 0.34 mole) be cooled to 0-5 ℃, gradually add anhydrous methanol (20 milliliters, about 0.1 mole) then, then divide secondary to add 3-(2-guanidine radicals-thiazole-4-base one methylthio group again) propionitrile (20.51 grams, 0.085 mole), simultaneously temperature is controlled at above-mentioned level.Stirred 20 hours down at 5 ℃, make it to dissolve fully.After this press the method described in the embodiment 5A, add methylene dichloride (300 milliliters), so that separate imido-ester to above-mentioned basic solution.Said mixture is stirred fully, finally obtains having the present invention's of same nature compound, and yield is 82%.Reclaiming some products that obtain from the methylene dichloride organic phase can use for recirculation.
(D) press the described method of embodiment 4A and 5A, replace 1 with 2-methyldioxane, 2-Yi Ji diox or 2-Ben Ji diox, the 4-diox obtains identical result thus.
Embodiment 6
3-(2-guanidine radicals-thiazole-4-base-methylthio group) third amidine
Will be by methyl-(2-guanidine radicals-thiazole-4-base-methylthio group) propionyl imido-ester (2.73 grams, 0.01 ammonium chloride (1.12 grams mole),, 0.021 the mixture heating up to 45 formed of methyl alcohol (2.5 milliliters) and acetonitrile (10 milliliters) ℃ mole),, allow it be cooled to room temperature then, stirred simultaneously 24 hours.Elimination ammonium chloride (0.58 gram, 1.09 moles) adds the hydrochloric acid-dioxan of equivalent again in solution, separate out thus that oily is heavy to revolve thing, places refrigerator, is solidified.After in ether, carrying out crystallization (by evaporation), obtain fusing point and be 183-187 ℃ product.
Embodiment 7
N, N-trimethyl silyl-methyl-3-(2-guanidine radicals-thiazole-4-base-methylthio group) propionyl imido-ester solution
(A) propionyl imido-ester (methyl-imido vinegar 3-trimethyl silyl-2-oxazolidone: at methyl-3-(2-guanidine radicals-thiazole-4-base-methylthio group), 27.3 gram, 0.1 add (50.5 milliliters of 3-TMSs-2-oxazolidone in acetonitrile (80 milliliters) suspension mole), 0.33 mole), stir on the limit, and the limit is heated to 65-75 ℃ gradually.After 15 minutes, be cooled to room temperature, obtain the compound shown in the present embodiment title thus.
(B) trimethylchlorosilane: by imido acid methyl esters (methylimidate, 27.3 gram, 0.1 mole), methylene dichloride (200 milliliters), triethylamine are (42.0 milliliters, 0.30 mole) and trimethylchlorosilane (34.76 grams, 0.32 mole) suspension of being formed promptly produces the compound shown in the present embodiment title after stirring certain hour under 30 ℃ the temperature.
Replace the silylation agent with trimethyl-silyl-imidazole quinoline ketone, then obtain identical result.
(C) N, N '-four-trimethyl silyl sulphonamide: by imido acid methyl esters (27.3 grams, 0.1 mole) and N ', N '-four-trimethyl silyl sulphonamide (38.4 grams, 0.1 mole) mixture in anhydrous dimethyl yl acetamide (80 milliliters) stirs very fast formation solution under 40 ℃ temperature.At short period of time (10 minutes) internal cooling to 33 ℃, then be chilled to room temperature more then, obtain the compound shown in the present embodiment title thus.
Replace the silylation agent with the trimethyl silyl phthalimide, then obtain same result.
(D) N, N '-two-trimethyl silyl ethanamide: use N, N '-two-trimethyl silyl ethanamide (65.0 grams, 0.32 mole) handles imido acid methyl esters (27.3 grams, 0.1 suspension in chloroform (100 milliliters) mole) stirs simultaneously and heats.Through certain hour, promptly produce the compound shown in the present embodiment title.Replace the silylation agent with hexamethyldisilazane, then obtain same result.
Embodiment 8
N-trimethyl silyl-N-sulfamyl-3-(2-guanidine radicals-thiazole-4-base-methylthio group)-third amidine
With methyl-3-(2-guanidine radicals-thiazole-4-base-methylthio group) propionyl imido-ester (10.94 grams, 0.04 mole) and N ', N '-two-trimethylammonium-silyl sulphonamide (28.85 grams, 0.12 mole) suspension in acetonitrile (32 milliliters) heats (about 45 minutes) lentamente and to 55-60 ℃, it is dissolved fully.Make temperature reduce to room temperature then, after stirring 70 hours under 20-25 ℃, confirm that by tlc no imido-ester exists, and generated the compound shown in the present embodiment title.
Embodiment 9
N-trimethyl silyl-N-sulfamyl-3-(2-guanidine radicals-thiazole-4-base-methylthio group) solution of third amidine, (from embodiment 7).
Press the described method of embodiment 7C, to the solution adding sulphonamide (19.2 grams, 0.2 mole) of gained.Stir after 24 hours, form the solution of the compound shown in the present embodiment title.With the disappearance of tlc control imido acid methyl esters and the generation of sulfamyl derivative.
Embodiment 10
The method of desilylation: the separation of Famotidine heavy stone used as an anchor (famotidine)
(A) under agitation, the reaction product to embodiment 8 adds methyl alcohol (9.0 milliliters, 0.22 mole) lentamente.After adding first methyl alcohol, produce and carry the contamination precipitation thing on a small quantity secretly.Fold colourless solution, continue to add pure liquid,, mixes with acetonitrile (30 milliliters), and proceed to stir curing separating of oil come out of separating out.After the filtration, use acetonitrile and washed with dichloromethane in succession, obtain the compound shown in 9.45 gram (70% clean yield) present embodiment titles at last.Infrared spectra (KBr) analysis revealed, feature indicating value are 3480, and 3360(light belt is 3380 and 3340), 3210,3080 and 2910cm
-1, be equivalent to the LMP polymorphic form.
(B) in the reaction product of embodiment 9, add Virahol (24.0 grams, 0.4 mole), use methylene dichloride (250 milliliters) dilution then, place ice one water-bath to cool off, simultaneously mixture is stirred.Help crystallization with the inoculation of Famotidine pyridine crystal.After the filtration, use washed with dichloromethane, drying separates obtaining the compound shown in the present embodiment title thus again, and its yield is identical with embodiment 10A's.
(C) use methyl alcohol (25 milliliters) to handle the solution of the method gained of pressing embodiment 8, under reduced pressure steam solvent then, reach about 25 milliliters until its volume.At room temperature stir, be settled out solid, after the filtration,, obtain the compound shown in the present embodiment title thus, and have identical yield with acetonitrile and washed with dichloromethane.
(D) under pH is 2 condition, separating the Famotidine pyridine hydrochloride that obtains from methyl alcohol is suspended in the alcohol once more, and the pH value is adjusted to 7.5 with triethylamine, obtain fusing point thus and be 165-173 ℃ polymorphic form, infrared spectra (KBr) analysis revealed, the feature indicating value in the 3500-3000 district are that 3400(light belt is 3430 and 3390), 3330,3220 and 3070cm
-1, X-ray diffraction spectrum is described identical with embodiment 10E.
(E) at room temperature, N,N-DIMETHYLACETAMIDE (10.0 milliliters) solution of Famotidine pyridine (5.0 gram) is added in the methylene dichloride (60.0 milliliters) gradually, fully stirs simultaneously.The solidified throw out was stirred 15 minutes, and after filtration, after washing and the drying, obtain 4.90 gram products, fusing point is 168-172 ℃ (the high-melting-point polymorphic form that is the conglomeration shape).Infrared spectra (KBr) ν cm
-1: the feature indicating value is that 3400(is a two-wire at 3430 and 3390 places), 3300,3220 and 3070.
X-ray diffraction pattern is 1.5405 dusts going into, and as source of radiation, records following characteristics value by siemens Kristalloflex 810 Interface DACO-Mp equipment (40 kilowatts of power, strength of current are 20 milliamperes) with copper:
D=spacing I/I
1=relative intensity
20.23 0.05
8.22 0.14
6.55 0.12
6.24 0.14
6.09 0.26
5.88 0.13
5.57 0.08
5.14 0.12
4.72 0.27
4.53 0.19
4.45 1.00
4.36 0.69
4.24 0.55
4.12 0.55
3.93 0.17
3.79 0.34
3.70 0.22
3.58 0.25
3.47 0.09
3.43 0.14
3.33 0.40
3.27 0.14
3.14 0.24
3.06 0.17
3.02 0.18
2.95 0.05
2.79 0.11
2.74 0.10
2.67 0.10
2.62 0.06
2.58 0.09
2.51 0.04
2.47 0.06
2.36 0.09
2.33 0.04
2.30 0.06
2.28 0.12
2.24 0.07
2.22 0.05
2.13 0.13
2.10 0.04
2.01 0.04
1.97 0.04
1.95 0.04
1.83 0.03
1.81 0.05
1.77 0.07
1.73 0.04
1.71 0.04
1.68 0.07
Claims (8)
1, a kind of method that is used to prepare Famotidine pyridine (famotidine) is characterized in that:
(a) make general formula be
Compound and acrylonitrile reactor, generate 3-(2-guanidine radicals-thiazole-4-base-methylthio group) propionitrile thus, R in the following formula
0Be hydrogen atom or C
1-C
3Alkyl, m is 2 to 7, and n is 2 to 4;
(b) make general formula be
Hydrogen-oxygen (in the general formula II, R
1Be hydrogen atom, methyl, ethyl or phenyl, O is 1 to 2, and p is 2 to 3, and X is chlorion, bromide anion, methylsulphonic acid root or trifluoromethane sulfonic acid root) replace propanenitrile derivatives reaction 8 to 20 hours with the 3-of formula I, generate following general formula III thus
Compound (R in the formula
0Definition the same, Z is a halogen atom), but in the presence of methyl alcohol, in the compound of the general formula III that is then produced, Z is a methoxyl group, and in the presence of ammonia or ammonium chloride, in the compound of the molecular formula III that is produced, Z is amino, and these compounds that produced also can be the forms with the represented acid salt of X in the formula II.
(c) compound and the silylation agent by the general formula III (is selected from N-silylamine, N-silyl acid amides, N-silyl sulphonamide or contains C
1-C
4The halogenated silanes of alkyl) reaction generates following general formula III
Silyl compound, R in the formula
0Definition the same, R is C
1-C
4The alkyl of straight or branched;
(d) under 20-60 ℃ temperature, make the compound and the following formula VI of general formula III or IV
Sulphonamide (in the formula definition of R the same, R
3Be hydrogen atom, R (CH
3)
2Si or C
1-C
4The alkyl silyl) reaction, generate following general formula V
Methyl compound (R in the formula
0The same with the definition of R).
(e) at room temperature, make the silyl compound (R is a hydrogen atom in the formula) and the C of general formula V
1-C
5The alcohol reaction of straight or branched, generate the Famotidine pyridine.
2, method according to claim 1, base is characterised in that R in the said formula I is that the series of compounds of hydrogen atom is prepared by following method: at room temperature promptly, make and be selected from isothiourea, the N-methyl-isothiourea, S-(2-guanidine radicals-the thiazole of above-mentioned this class material of amidino groups isothiourea or xanthogenate-4-base-methyl) a kind of compound in the derivative (is selected from acetonitrile at solvent, Virahol or their mixture) in the water of equivalent, mineral alkali (as sodium hydroxide or potassium hydroxide), organic bases is (as triethylamine, diethylamine) or acyclic amidines (as tetramethyl guanidine or pentamethyl-guanidine) or bicyclic amidine react and make.
3, method according to claim 1 is characterized in that R in the said formula I
OBe hydrogen atom series of compounds at room temperature, by 2-guanidine radicals-4-mercapto methyl-thiazole in solvent (being selected from acetonitrile, propyl alcohol or their mixture) with the reaction of the bicyclic amidine of equivalent and prepare.
4, method according to claim 1 is characterized in that the salt system of said formula I is selected from the salt of following amidine class, that is: 1, and 8-diaza-bicyclo [5,4,0] 11 carbon-7-alkene or 1,5-diaza-bicyclo [4,3,0] ninth of the ten Heavenly Stems-5-alkene.
5, method according to claim 1, it is characterized in that (wherein R is a hydrogen atom for the hydrogen-oxygen salt of said general formula II, O=1, p=3, perhaps O=p=2) be to be selected from 1,3-diox or 1, the 4-diox, and X is chlorion or bromide anion, its You diox and hydrochloric acid or Hydrogen bromide react and make, with prepared concentration is hydrogen-oxygen and the 3-(2-guanidine radicals-thiazole-4-base-methylthio group of 20%-30%) propionitrile (both mol ratios are 1: 3 to 1: 7) reacted 6 to 20 hours under 3 °-10 ℃ temperature, generated the compound (R of general formula III thus
0Be hydrogen atom, Z is the chlorine or bromine atom), perhaps make above-mentioned hydrogen-oxygen and methyl alcohol reaction (both mol ratios are 1: 4 to 1: 7), in the compound of the general formula III that is then generated, Z is a methoxyl group.
6, method according to claim 1 is characterized in that the compound (R of said general formula III
0Be hydrogen atom) or its acid salt (be selected from vitriol, metilsulfate, trifluoromethyl sulfonic acid, muriate or bromide) (be selected from this group of forming by following compound any with the silylation agent, that is: hexamethyldisilazane, 3-trimethyl silyl-2-oxazolidone, 1,3-pair-the trimethyl silyl urea, N, O-pair-the trimethyl silyl ethanamide, N-trimethyl silyl ethanamide, N-trimethyl silyl saccharin, N-trimethyl silyl phthalimide, N-trimethyl silyl biuret, N-trimethyl silyl pyrroles, N-trimethyl-silyl-imidazole quinoline, trimethylchlorosilane, chlorotriethyl silane, the tripropyl chlorosilane, dimethyl tertiary butyl chloride silane, N, O-pair-the trimethyl silyl sulphamide) reaction, obtain the solution of the silyl compound of general formula IV thus, the latter and N-trimethyl silyl sulfuryl amine reaction, (wherein R can be C to the compound of generation general formula V
1-C
4Alkyl).
7, method according to claim 1 is characterized in that compound or its additive salt (R of said general formula III
0Be hydrogen atom) (be selected from N with the compound of general formula VI, N '-two-trimethyl silyl sulphonamide, N, N '-four-trimethyl silyl sulphonamide, N, N '-two-dimethyl-tertiary butyl silyl sulphonamide, N, N '-two triethylsilyl sulphonamide or N, N-pair-tripropyl silyl sulphonamide), at inert solvent (non-hydroxyl solvent, preferably be selected from acetonitrile, diox, N,N-DIMETHYLACETAMIDE, methylene dichloride or chloroform) in react, obtain general formula V (R in the formula thus
0Be hydrogen atom, the definition of R is the same) silyl compound solution.
8, method according to claim 1, base is characterized in that the compound solution (R in the formula of said general formula V
0Be hydrogen atom, R is a methyl) react with alcohol (being selected from methyl alcohol, Virahol or propyl carbinol), generate the Famotidine pyridine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES8800205A ES2008962A6 (en) | 1987-12-17 | 1987-12-17 | New-quanidino-thiazol compounds, their preparation, and use as intermediates of famotidine process. |
| ES8800205 | 1987-12-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1033521A true CN1033521A (en) | 1989-06-28 |
Family
ID=8254599
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN88104081A Pending CN1033521A (en) | 1987-12-17 | 1988-06-29 | Novel 2-guanidine radicals thiazolium compounds and preparation method thereof, and the intermediate that is used as Famotidine pyridine preparation technology |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0322335A1 (en) |
| JP (1) | JPH01172378A (en) |
| KR (1) | KR910002877B1 (en) |
| CN (1) | CN1033521A (en) |
| DK (1) | DK354188D0 (en) |
| ES (1) | ES2008962A6 (en) |
| FI (1) | FI884338A0 (en) |
| IL (1) | IL86649A0 (en) |
| IS (1) | IS3359A7 (en) |
| NO (1) | NO882562D0 (en) |
Cited By (1)
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|---|---|---|---|---|
| CN101081839B (en) * | 2006-06-02 | 2010-12-29 | 范敏华 | Refining technique of famotidine raw material |
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| US6777217B1 (en) | 1996-03-26 | 2004-08-17 | President And Fellows Of Harvard College | Histone deacetylases, and uses related thereto |
| US5856500A (en) * | 1997-03-11 | 1999-01-05 | Albemarle Corporation | Synthesis of thiazole derivatives |
| US5731442A (en) * | 1997-03-11 | 1998-03-24 | Albemarle Corporation | Synthesis of thiazole derivatives |
| US20030129724A1 (en) | 2000-03-03 | 2003-07-10 | Grozinger Christina M. | Class II human histone deacetylases, and uses related thereto |
| US7244853B2 (en) | 2001-05-09 | 2007-07-17 | President And Fellows Of Harvard College | Dioxanes and uses thereof |
| CA2426122A1 (en) * | 2002-05-02 | 2003-11-02 | M/S Tonira Pharma Limited | A process for the preparation of a combination of famotidine polymorphis a and b |
| CN101495116A (en) | 2005-03-22 | 2009-07-29 | 哈佛大学校长及研究员协会 | Treatment of protein degradation disorders |
| JP5409015B2 (en) | 2006-02-14 | 2014-02-05 | プレジデント アンド フェロウズ オブ ハーバード カレッジ | Histone deacetylase inhibitor |
| WO2008091349A1 (en) | 2006-02-14 | 2008-07-31 | The President And Fellows Of Harvard College | Bifunctional histone deacetylase inhibitors |
| AU2007248656B2 (en) | 2006-05-03 | 2013-04-04 | Dana-Farber Cancer Institute, Inc. | Histone deacetylase and tubulin deacetylase inhibitors |
| RU2515611C2 (en) | 2008-07-23 | 2014-05-20 | Президент Энд Феллоуз Оф Гарвард Колледж | Deacetylase inhibitors and their application |
| WO2011019393A2 (en) | 2009-08-11 | 2011-02-17 | President And Fellows Of Harvard College | Class- and isoform-specific hdac inhibitors and uses thereof |
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| DK160611C (en) * | 1979-09-04 | 1991-09-16 | Bristol Myers Squibb Co | ANALOGY PROCEDURE FOR PREPARING 3,4-DISUBSTITUTED 1,2,5-THIADIAZOL-1-OXIDES AND -1,1-DIOXIDES |
-
1987
- 1987-12-17 ES ES8800205A patent/ES2008962A6/en not_active Expired
-
1988
- 1988-03-23 EP EP88500031A patent/EP0322335A1/en not_active Withdrawn
- 1988-05-06 JP JP63110322A patent/JPH01172378A/en active Pending
- 1988-06-03 KR KR1019880006697A patent/KR910002877B1/en not_active IP Right Cessation
- 1988-06-07 IL IL86649A patent/IL86649A0/en unknown
- 1988-06-10 NO NO882562A patent/NO882562D0/en unknown
- 1988-06-14 IS IS3359A patent/IS3359A7/en unknown
- 1988-06-27 DK DK354188A patent/DK354188D0/en not_active Application Discontinuation
- 1988-06-29 CN CN88104081A patent/CN1033521A/en active Pending
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101081839B (en) * | 2006-06-02 | 2010-12-29 | 范敏华 | Refining technique of famotidine raw material |
Also Published As
| Publication number | Publication date |
|---|---|
| IS3359A7 (en) | 1989-02-15 |
| DK354188D0 (en) | 1988-06-27 |
| EP0322335A1 (en) | 1989-06-28 |
| ES2008962A6 (en) | 1989-08-16 |
| NO882562D0 (en) | 1988-06-10 |
| KR890009899A (en) | 1989-08-04 |
| IL86649A0 (en) | 1988-11-30 |
| KR910002877B1 (en) | 1991-05-09 |
| JPH01172378A (en) | 1989-07-07 |
| FI884338A0 (en) | 1988-09-21 |
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